Infections with RNA or DNA viruses are a significant threat for the health of man and animal. For instance, infections with influenza viruses do still belong to the big epidemics of mankind and cause year for year a big number of casualties. In terms of the national economies, they are an immense cost factor, for instance due to unfitness for work. Infections with the Borna disease virus (BDV), which mainly affects horses and sheep, but which has also been isolated for humans and is connected to neurological diseases, equally have an enormous economic importance.
The problem of controlling in particular RNA viruses is the adaptability of the viruses caused by a high fault rate of the viral polymerases, which makes the production of suitable vaccines as well as the development of antiviral substances very difficult. Furthermore it has been found that the application of antiviral substances immediately directed against the functions of the virus, shows a good antiviral effect at the beginning of the treatment, but will quickly lead to the selection of resistant variants based on mutation. An example is the anti-influenza agent amantadine and its derivatives directed against a transmembrane protein of the virus. Within a short time after the application, resistant variants of the virus are generated. Other examples are the new therapeuticals for influenza infections inhibiting the influenza-viral surface protein neuraminidase. To these belongs for instance Relenza. In patients, Relenza-resistant variants have already been found (Gubareva et al., J Infect Dis 178, 1257-1262, 1998). Hopes placed in this therapeutical could therefore not be fulfilled.
Because of the very small genome and thus limited coding capacity for functions being necessary for the replication, all viruses are dependent to a high degree from functions of their host cells. By exertion of influence on such cellular functions being necessary for the viral replication, it is possible to negatively affect the virus replication in the infected cell. Herein, there is no possibility for the virus to replace the lacking cellular function by adaptation, in particular by mutations, in order to thus escape from the selection pressure. This could already be shown for the influenza A virus with relatively unspecific inhibitors against cellular kinases and methyl transferases (Scholtissek and Müller, Arch Virol 119, 111-118, 1991).
It is known in the art that cells have a multitude of signal transmission paths, by means of which signals acting on the cells are transmitted into the cell nucleus. Thereby the cell is capable to react to external stimuli and to react by cell proliferation, cell activation, differentiation, or controlled cell death. It is common to these signal transmission paths that they contain at least one kinase activating by phosphorylation at least one protein subsequently transmitting a signal. When observing the cellular processes induced after virus infections, it is found that a multitude of DNA and RNA viruses preferably activate in the infected host cell a defined signal transmission path, the so-called Raf/MEK/ERK kinase signal transmission path (Benn et al., J Virol 70, 4978-4985, 1996; Bruder and Kovesdi, J Virol 71, 398-404, 1997; Popik and Pitha, Virology 252, 210-217, 1998; Rodems and Spector, J Virol 72, 9173-9180, 1998). This signal transmission path is one of the most important signal transmission paths in a cell and plays a significant role in proliferation and differentiation processes. Growth factor-induced signals are transmitted by successive phosphorylation from the serine/threonine kinase Raf to the dual-specific kinase MEK (MAP kinase kinase/ERK kinase) and finally to the kinase ERK (extracellular signal regulated kinase). Whereas as a kinase substrate for Raf, only MEK is known, and the ERK isoforms were identified as the only substrates for MEK, ERK is able to phosphorylate a whole number of substrates. To these belong for instance transcription factors, whereby the cellular gene expression is directly influenced (Cohen, Trends in Cell Biol 7, 353-361, 1997; Robinson and Cobb, Curr. Opin. Cell Biol 9, 180-186, 1997; Treisman, Curr. Opin. Cell Biol 8, 205-215, 1996).
The drawback of prior art antiviral active substances is that they are either directed against a viral component and thus quickly lead to resistances (cf. amantadine), or act in a too broad and unspecific manner against cellular factors (for example methyl transferase inhibitors), and significant side effects are to be expected. Consequently, none of the substances being active against cellular factors is known to have been developed to a therapeutical for virus diseases. On the other hand, the inhibition of other kinases, for instance the inhibition of the kinase JNK of the MEKK/SEK/JNK signal transmission path, can increase the virus multiplication. Further it is known that the increased activation of again other kinases, for instance of the protein kinase C (PKC), inhibits the replication of viruses (Driedger and Quick, WO 92/02484).
With regard to the cellular processes induced after a virus infection, it is found that a multitude of DNA and RNA viruses activate, in the infected host cell, a defined signal transduction pathway, the so-called Raf/MEK/ERK kinase cascade.
This kinase cascade belongs to the most important signaling pathways in the cell and plays an essential role in proliferation and differentiation processes.
Growth-factor induced signals are transferred by successive phosphorylation from the serine/theorine kinase Raf to the dual specific kinase MEK (MAP kinase kinase/ERK kinase) and finally to the kinase ERK (extracellular signal regulated kinase). Whilst as a kinase substrate of Raf, only MEK is known, and the ERK isoforms have been identified for MEK as the only substrate, ERK can phosphorylate quite a number of substrates. Hereto belong for instance the phosphorylation of transcription factors, which leads to a direct modification of the cellular gene expression.
The investigation of this signaling pathway in cellular decision processes has led to the identification of several pharmalogical inhibitors, which inhibit the signaling pathway, among other positions, on the level of MEK, i.e. at the ‘bottleneck’ of the cascade.
The MEK inhibitor PD98059 inhibits the activation of MEK by the kinase Raf.
The MEK inhibitor PD184352 has been described (2-(2-chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide), which with oral administration in the mouse model could efficiently inhibit the growth of colon carcinoma.
The MEK inhibitor AZD6244 (Selumetinib) is a drug being investigated for the treatment of various types of cancer, for example non-small cell lung cancer (NSCLC).
AZD8330 is an orally active, selective MEK inhibitor with an IC50 of 7 nM. AZD8330 has potential antineoplastic activity. AZD8330 specifically inhibits mitogen-activated protein kinase kinase 1 (MEK or MAP/ERK kinase1), resulting in inhibition of growth factor-mediated cell signaling and tumor cell proliferation.
The MEK inhibitor RDEA-119 (BAY-869766) has been shown to be a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer.
The MEK inhibitor GSK-1120212 (Trametinib) is a potent and selective allosteric inhibitor of the MEK1 and MEK2 (MEK1/2) enzymes with promising antitumor activity in a phase I clinical trial (ASCO 2010).
TAK-733 is a potent, selective, ATP-noncompetitive MEK allosteric site inhibitor with an 1050 of 3.2 nM.
The MEK inhibitor RO5126766 is a protein kinase inhibitor specific for the Raf and MEK mitogen-activated protein kinases (MAPKs) with potential anti-neoplastic activity. Raf/MEK dual kinase inhibitor RO5126766 specifically inhibits the kinase activities of Raf and MEK, resulting in the inhibition of target gene transcription that promotes malignant transformation of cells.
The MEK inhibitor AS703026 is a novel, highly selective and potent allosteric inhibitor of MEK1/2 which is currently under Phase II clinical trial for acute myeloid leukemia.
The MEK inhibitor PLX-4032 (Zelboraf® (Vemurafenib)) is market for the treatment of late-stage melanoma.
The MEK inhibitors CI-1040, PD0325901, AZD6244, GDC-0973, RDEA119, GSK1120212, AZD8330, RO5126766, RO4987655, TAK-733 and AS703026 are known in the art and, for example, described in Table 1 and shown in FIG. 4 of Fremin and Meloche (2010), J. Hematol. Oncol. 11; 3:8.
Neuraminidase (also known as sialidase, acylneuraminyl hydrolase, and EC 3.2.1.18) is an enzyme common among animals and a number of microorganisms. It is a glycohydrolase that cleaves terminal alpha-ketosidically linked sialic acids from glycoproteins, glycolipids and oligosaccharides. Many of the microorganisms containing neuraminidase are pathogenic to man and other animals including fowl, horses, swine and seals. These pathogenic organisms include influenza virus.
Neuraminidase has been implicated in the pathogenicity of influenza virus. It is thought to help the elution of newly synthesized virons from infected cells and assist in the movement of the virus (through its hydrolase activity) through the mucus of the respiratory tract.
A class of specific anti-influenza agents, the neuraminidase inhibitors, has demonstrated inhibition of both influenza A and B viruses. Oseltamivir is used for the treatment of viral infections; however, it does not treat nasal congestion. Oseltamivir is the ethyl ester prodrug of the carbocyclic transition state sialic acid analog RO 64-0802 (GS4071), a potent and selective inhibitor of influenza A and B virus neuraminidases. Oral oseltamivir has been approved for treatment of acute influenza in the United States in 1999. It has demonstrated efficacy both in treating and preventing influenza illness.
Oseltamivir phosphate is a prodrug of oseltamivir carboxylate (oseltamivir), an inhibitor of the neuraminidase glycoprotein essential for replication of influenza A and B viruses. Oseltamivir is available from Roche Pharma™ AG (Switzerland). Alternatively, oseltamivir can be prepared according to the methods described in U.S. Pat. No. 5,763,483 to Bischofberger et al and U.S. Pat. No. 5,866,601 to Lew et al. About 10-15% of patients taking oseltamivir experience nausea and vomiting. Patients with kidney dysfunction should take lower doses.
Zanamivir (Relenza) is an orally inhaled powder currently approved in 19 countries for the treatment of, and in two for the prophylaxis of influenza A and B. Zanamivir is a competitive inhibitor of the neuraminidase glycoprotein, which is essential in the infective cycle of influenza viruses. It closely mimics sialic acid, the natural substrate of the neuraminidase. Over the last few years, a number of events have resulted in changes to the zanamivir prescribing information which now contains warnings of bronchospasm, dyspnea, rash, urticaria and allergic type reactions, including facial and oropharyngeal oedema.
Peramivir is a neuraminidase inhibitor, acting as a transition-state analogue inhibitor of influenza neuraminidase and thereby preventing new viruses from emerging from infected cells.
It is known that neuraminidase inhibitors are not effective for all influenza viruses and a resistance can be developed by new generation of influenza virus strain.
In view of the prior art, it is clear that there is the need of compounds and compositions effective in the treatment of virus diseases in particular in diseases caused by influenza virus.